Currently, Alzheimer's disease (AD), a leading cause of dementia, develops in one percent of the population between the ages 65 and 69, and increasing to 40-50% in those 95 years and older. AD patients exhibit telltale clinical symptoms that include cognitive impairment and deficits in memory function. In the current working model, there are three ‘stages’ that are associated with AD. First, neuronal cells become sick as a result of synaptic/metabolic malfunctioning that leads to neuronal deficiencies. Secondly, in the histological stage, an accumulation of neurofibrillary tangles and beta amyloid plaques begins, leading to the untimely aggregation of insoluble proteins in the brain. Finally, AD ultimately causes neuronal death and shrinkage in brain volume. AD patients typically have a heavy senile plaque (SP) burden found in the cerebral cortex which is verified by postmortem histopathological examination. SPs are extracellular deposits containing β-amyloid peptide cleaved from a longer amyloid precursor protein to produce a 40-43 amino acid peptide. Amyloid aggregates in brain play a key role in a cascade of events leading to AD. Interestingly, despite the development and presence of senile plaques in elderly persons with normal cognitive function, the severity of NFT and senile plaque deposition purportedly correlates with a loss of cognitive function and neuronal circuitry deterioration.
Major neuropathology observations of postmortem examination of AD brains confirm the presence of AD through the detection of extracellular β-amyloid peptides and intracellular neurofibrillary tangles (NFT). NFTs derive from filaments of hyperphosphorylated tau proteins. The presence and severity of NTFs correlate with severity of dementia and cognitive impairment (Dickinson, D. W., Neurobiol. Aging 1997, 18 [4 suppl]:S21-S26). The pathological process of AD must begin before the presentation of the clinical symptoms of dementia.
Despite Alzheimer's disease being the fourth leading cause of death in the United States, pharmaceutical intervention has yet to commercialize a curative therapy. Recently, Marwan N. Sabbagh published an overview of the current state of clinical development of AD pharmacotherapy (The American Journal of Geriatric Pharmacotherapy, 2009, 7(3), p. 167). Encouraging results from completed Phase II trials of dimebon, huperzine A, intravenous immunoglobulin, and methylthioninium chloride were reported at ICAD 2008. Nineteen compounds are currently in Phase II trials, and 3 compounds (AN1792, lecozotan SR, and SGS742) failed at this stage of development.
In addition to pharmaceutical approaches for curbing the effects of AD, researchers are attempting to detect AD by other means, including establishing technologies for early detection. Currently, there are many strategies that attempt to identify AD-associated pathologies by targeting either the cell sickness or histological stages of the disease. There is an array of AD imaging agents that potentially confirm the well-established manifestation of AD, however, this late stage diagnosis offers little defense against further disease progression past 36 months. Interestingly, the detection of senile plaques and tangles in the brain may not necessarily prove that a patient has developed AD.
As summarized from a recent discussion group on Dec. 5, 2006 (Biochemical Pharmacology Discussion Group, cosponsored by the American Chemical Society's New York section), researchers are now focusing on methods that target AD precursors by blocking either β-amyloid protein (BAP) production or by controlling mutant tau protein formation. Clearly, this focused research effort aims to control the formation of AD precursors that potentially lead to AD and this new strategy might delay full-onset AD more effectively that current therapeutics. In parallel, neurological imaging must mirror the therapeutic trend by identifying AD precursors in a duel effort to compliment both AD therapeutic development and, in addition, identify presymptomatic at-risk AD patients. Recent drug development has been aimed at preventing the accumulation of SPs and NFTs in presymptomatic AD patients. The ability to measure levels of these lesions in the living human brain is thus desirable for presymptomatic diagnosis of AD and also for monitoring the progression of the disease.
Unfortunately, since AD cannot be confirmed in the patients until a histological examination is performed, understanding the link between the uptake of these tracers and the relevant biochemical processes involved could remain unsolved for many years.
Thus, in vivo imaging of NFTs in conjunction with imaging SPs could prove useful for the early and accurate diagnosis of AD. Quantitative evaluation of tau pathology could also be helpful for tracking severity of dementia, because the formation of neuritic pathology correlates well with clinical severity of dementia (Dickson, 1997). NFT deposition in the entorhinal cortex is closely associated with neuronal loss in very early AD patients (Gomez-Isla et al., 1996). If novel treatments that prevent the pathological formation of neurofibrillary pathology could be turned into clinical applications, this imaging technique would be applicable for the evaluation of treatment efficacy.
Currently, neurological imaging of AD has seen the emergence of imaging tracers that appear to confirm the presence of AD based on plaque and fibril mediated tracer uptake and, subsequently, are currently undergoing extensive clinical examination. Many of these tracers contain chemotypes that are derived from fluorescent dyes.
Potential ligands for detecting Aβ aggregates in the living brain must cross the intact blood-brain barrier. Thus brain uptake can be improved by using ligands with relatively smaller molecular size and increased lipophilicity.
Previous neuropathological research suggests that the deposition of NFTs occurs before the presentation of clinical symptoms of AD. Even in the very early stages of AD, patients display considerable numbers of NFTs in the entorhinal cortex and hippocampus, sufficient for the neuropathological diagnosis of AD. Thus, in vivo imaging of NFTs in conjunction with imaging SPs could prove useful for the early and accurate diagnosis of AD, for monitoring the progression of the disease and for evaluation of treatment efficacy.
Optimization of current candidates and discovery of novel compounds that specifically bind tau or Aβ aggregates are of high interest for development of in vivo tau− and Aβ imaging agents for detection of neurological disorders, and inparticular for imaging and detection of AD in patients.